This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The role of SIV-specific cellular immune responses in maintaining nonpathogenic SIV infection in sooty mangabeys is being investigated using Elispot and intracellular cytokine staining assays as well as by in vivo CD8-positive T lymphocyte depletion studies. In vivo CD8 depletion using the mouse-human chimeric anti-CD8 mAB cM-T807 resulted in a two-log or greater increase in SIV viremia in 5/6 mangabeys. Return of SIV viremia levels to baseline values was coincident with recovery of peripheral CD8-positive T lymphocytes. These data suggest that CD8-positive T lymphocytes do inhibit SIV replication in vivo in SIV-infected sooty mangabeys. In a cross-sectional analysis, positive SIV-specific interferon-gamma Elispot responses ranging between 510-5244 spot forming cells per million PBMC were observed in 25/25 SIV-infected mangabeys and were comparable to that observed in 13 rhesus macaques infected for more than one year with SIVmac251. In the majority of sooty mangabeys, the interferon-gamma responses to SIV Gag and/or Env proteins accounted for at least two-thirds of the total SIV-specific response. In 9 mangabeys examined, the interferon-gamma responses to Gag and Env were predominantly mediated by high avidity CD8-positive T lymphocytes. Naturally SIV-infected sooty mangabeys mount a substantial SIV-specific cellular immune response, suggesting that immune tolerance is neither a feature nor a requirement for maintenance of nonpathogenic infection in this natural host of SIV infection.